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Bovine Metabolic Diseases CS 712, Food Animal Medicine Matt D. Miesner, DVM, MS, DACVIM (LAIM) Asst. Professor, Clinical, Ag. Practices Contacts: Office I-107, phone: 532-4231, [email protected] There are essentially 4 big metabolic diseases that we will discuss during this block of lecture. The big 4 are Hypocalcemia, Hypophosphatemia, Hypomagnesemia, and Negative Energy Balance (Ketosis). Fatty liver syndrome as a result of negative energy balance will be discussed in liver diseases section by Dr. Jones. A 5 th metabolic syndrome that we will discuss briefly is Hypokalemia as merely a recognition of risk factors, diagnosis and attempted therapy. Objectives: 1. Discuss major electrolytes involved with metabolic diseases in cattle. 2. Understand and apply pathophysiology of metabolic diseases for: a. Recognition of clinical signs b. Understanding how this/these animal(s) acquire the problem. c. Treatment options d. Recognize response to therapy or reason why they may not be responding. Recommended Reading: Current Vet Therapy 5;Food Animal Practice. Section II: Metabolic diseases; pp130- 144. Anderson, Rings (eds), Saunders Elsevier, 2009 St. Louis, MO. The July 2000 issue of the VCNA;Food Animal Practice also provides a comprehensive detailed resource for further understanding the general overview that will be presented in lecture. The exam will cover what is emphasized in lecture. However use this resource to help clarify any confusion you may have during lecture since the material is primarily derived from this source. 1. Goff JP. Pathophysiology of calcium and phosphorus disorders. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):319-337. 2. Martens H, Schweigel M. Pathophysiology of grass tetany and other hypomagnesemias. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):339- 368. 3. Herdt TH. Ruminant adaptation to negative energy balance; Influences on the etiology of ketosis and fatty liver. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):215-230. 4. Coffer NJ, Frank N, Elliott SB, et al. Effects of dexamethazone and isoflupredone acetate on plasma potassium concentrations and other biochemical measurements in dairy cows in early lactation. 2006 AJVR;67(7):1244-1251.

Bovine Metabolic Diseases

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Page 1: Bovine Metabolic Diseases

Bovine Metabolic Diseases CS 712, Food Animal Medicine

Matt D. Miesner, DVM, MS, DACVIM (LAIM) Asst. Professor, Clinical, Ag. Practices Contacts: Office I-107, phone: 532-4231, [email protected] There are essentially 4 big metabolic diseases that we will discuss during this block of lecture. The big 4 are Hypocalcemia, Hypophosphatemia, Hypomagnesemia, and Negative Energy Balance (Ketosis). Fatty liver syndrome as a result of negative energy balance will be discussed in liver diseases section by Dr. Jones. A 5th metabolic syndrome that we will discuss briefly is Hypokalemia as merely a recognition of risk factors, diagnosis and attempted therapy.

Objectives: 1. Discuss major electrolytes involved with metabolic diseases in cattle. 2. Understand and apply pathophysiology of metabolic diseases for:

a. Recognition of clinical signs b. Understanding how this/these animal(s) acquire the problem. c. Treatment options d. Recognize response to therapy or reason why they may not be

responding. Recommended Reading: Current Vet Therapy 5;Food Animal Practice. Section II: Metabolic diseases; pp130-144. Anderson, Rings (eds), Saunders Elsevier, 2009 St. Louis, MO.

The July 2000 issue of the VCNA;Food Animal Practice also provides a comprehensive detailed resource for further understanding the general overview that will be presented in lecture. The exam will cover what is emphasized in lecture. However use this resource to help clarify any confusion you may have during lecture since the material is primarily derived from this source.

1. Goff JP. Pathophysiology of calcium and phosphorus disorders. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):319-337.

2. Martens H, Schweigel M. Pathophysiology of grass tetany and other hypomagnesemias. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):339-368.

3. Herdt TH. Ruminant adaptation to negative energy balance; Influences on the etiology of ketosis and fatty liver. Vet. Clin North Amer: Food Animal Pract. 2000 July;16(2):215-230.

4. Coffer NJ, Frank N, Elliott SB, et al. Effects of dexamethazone and isoflupredone acetate on plasma potassium concentrations and other biochemical measurements in dairy cows in early lactation. 2006 AJVR;67(7):1244-1251.

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Calcium. (“Milk Fever”) When the discussion of calcium metabolism and disease arises in relation to cattle, it is invariably that of LOW circulatory and/or body stores of calcium. As far as I’m aware, hypercalcemia only occurs with calcinogenic glycoside poisoning from plants (uncommon), experimentally induced hyperparathyroidism, and iatrogenic (too much IV calcium, or too much exogenously administered vitamin D). We will therefore focus our discussion on hypocalcemia, commonly known as “Milk Fever” or “Parturient Paresis”. Calcium Homeostasis:(See Figure 1) Entire Extracellular pool of Calcium is about 10 grams (9-11g). Normal plasma calcium is 8.5-10mg/dl when measured during serum chemistry analysis which means that a 600kg cow has about 3 grams of calcium in her plasma pool. So what does that mean? Well, consider that a cow loses somewhere between 20 and 50 grams of calcium per day in milk and colostrum, and additional calcium is lost through the GI and urinary system. How does she maintain adequate calcium? Answer, dietary absorption and bone resorption through regulated hormonal influences of various feedback mechanisms. This should serve as merely a review and study guide for boards, I won’t expect you to regurgitate this on this exam. I will, however expect you to apply the concept while considering causal mechanisms and treatment of milk fever when faced with a clinical problem.

 

Figure 1:  Flow chart example of calcium regulation in an adult (~500kg) dairy cow.  Chart adapted from: Goff, JP. 

VCNA‐FAP, Jul 2000, 16(2), p320. PTH=parathyroid hormone, CT=calcitonin 

*What stimulates PTH secretion? *What is its affects on Ca++ homeostasis? *What stimulates 1,25-(OH2) vit D production? *How does it help maintain Ca++ levels?

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By answering the questions in the text box above, we can now begin to understand why the mechanism might fail, and risk factors leading to clinical cases of milk fever.

Factors altering PTH homeostasis o Hypomagnesemia- Blunts PTH secretion in response to ↓Ca++, as well

as interfering with PTH action (enzymatic) at tissue level. Potential dietary Mg deficiencies may therefore need to be investigated as a cause for milk fever in certain situations. More on magnesium below.

o Metabolic Alkalosis- Predisposes to hypocalcemia by altering the conformation of PTH receptors in bone and kidney cells. The key no longer fits the lock. During the fluid therapy lecture, we will discuss that the sick adult bovine is frequently in metabolic alkalosis, particularly with GI diseases (ie displaced abomasum, vagal indigestion, etc). In addition, nutrition plays an important vital part in the acid-base status of cattle. Feeding anionic salts, which keeps the blood pH on the acidic side is very effective in reducing cases of milk fever. Dr. Jones will discuss dietary cation-anion difference in depth.

o Age- Older cows have fewer osteoblasts and fewer PTH receptors at target tissues.

Factors altering 1,25-(OH2) vit D o Metabolic Alkalosis - Reduces renal sensitivity to PTH which normally

up-regulates production of vitD and increases GI absorption of Ca++. o High blood Phosphorus- Inhibits 25-hydroxyvitamin D-hydroxylase

enzyme for formation of vit D. Dietary formulations should not need to exceed a delivery rate of more than 35-45 g of P per day. Several studies have shown that feeding higher levels of P can increase the incidence of milk fever. Diets commonly contain 0.4 to 0.5% dietary P.

o Dietary Vitamin D deficiency- Unlikely but possible. Normal supplemental rate in feed is 20K to 30K IU per day. To determine if a deficiency exists, measure plasma 25-hydroxyvitamin-D levels (normal=20-50ng/ml)

o Vitamin D Excess- Suppresses endogenous mechanisms and extremely high doses (toxicity) may result in metastatic calcification of tissues. Was historically an attempted method to prevent milk fever, but not practical and presented risk of toxicity.

o Individual cow variation in timely production- Delayed synthesis of 1,25-(OH2) vit D, is seen in some cows during sudden high demand at calving. One reason for relapsing episodes of Milk Fever.

o Age- 1,25-(OH2) vit D receptors in intestine decline.

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Diagnosis: History, Signalment, Clinical Signs, response to Therapy. History and Signalment: Dairy Cows: Most often aged cows at calving. Not first differential in heifers (see above) unless severe dietary imbalances. “Channel Island” breeds more sensitive (ie Jersey and Guernsey breeds). Beef Cows: Not common, pathologic fractures would be more common and due to severe dietary deficiencies such as energy and/or protein malnutrition. Hypocalcemia is not common as an isolated syndrome but will occur in conjunction with Magnesium deficiency (see below). Clinical signs: DO A COMPLETE PHYSICAL EXAM. Want to rule out instigating causes (metritis/mastitis/pneumonia, etc) or consequences of milk fever (musculoskeletal injuries) Clinical signs are progressive and staged based on the degree of calcium deficiency. Observed clinical signs are related to the effects of low calcium neuromuscular and cardiovascular systems. Initial cell membrane instability results in hyperexitability and shaking followed by inhibited acetylcholine release (a function of calcium) resulting in flaccid paralysis. Reduced cardiac output/contractility results in poor perfusion of extremities making them feel cold to the touch. Stage 1. (Serum calcium ~ 5.5-7.5 mg/dl) -Able to stand, hyperexcitable, tremors (head, triceps, loin flanks), unsteady, treading feet, restless, open mouth breathing. Stage 2. (Serum calcium ~ 3.5-6.5 mg/dl) -Sternal recumbency, depressed, weak, head and neck curved around to flank, hypothermia, dilated pupils, delayed PLR, decreased anal tone, decreased heart sounds, rapid pulse, rumen stasis/bloat, poor anal sphincter tone. Stage 3. (Serum calcium ~ 2 – 3.5 mg/dl) -Lateral recumbency, unable to get to sternal, flaccid paralysis, bloat, poor laryngeal tone (may aspirate)

Treatment: IV Calcium borogluconate (23%). 1gm/100 lbs of body weight. Commercially available solutions come in 500ml bottles containing 10.7gm of calcium. Give a full bottle, avoid dextrose solutions when treating (alters P levels). Administer slowly while palpating auricular pulse. Pulse intensity should increase and heart rate decrease during treatment. Response to therapy will show reversal of clinical signs. Subcutaneous Calcium. After IV to sustain release Oral Products also available.

Prevention: Evaluate Dietary Practices/rations, especially in multiple or repeat cases.

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Phosphorus Phosphorus plays a huge role in body function as a part of phospholipids, phosphoproteins, nucleic acids, ATP, acid-base buffering, etc. It is important to consider phosphorus homeostasis in close context with that of calcium as they are frequently entwined in disease processes and each frequently has an effect on the other. Again, as with calcium, we consider hypophosphatemia related problems more frequently than hyperphosphatemia. Maintaining phosphorus is again dependent upon dietary absorption and bone resorption. A large portion of P is secreted through saliva is recovered through GI absorption. Elevated serum phosphorus when seen in cattle is a reflection of either anorexia, massive rumen flora die-off (microbes high in P), and lastly renal disease. Unlike monogastrics where hyperphosphatemia is a prompt indicator of renal disease, cattle have a great capacity to eliminate plasma phosphorus through salivary metabolism and excretion. Think of cattle having a second set of kidneys (salivary glands) which are, indeed, under the same hormonal influences as the kidneys. Plasma phosphorus concentrations are considered directly related to dietary availability and absorption. A summary of phosphorus homeostasis can be reviewed (figure 2). Notice the shared hormonal influences between calcium and phosphorus.

 

Figure 2:  Flow chart example of phosphorus regulation in a cow.  Chart adapted from:  Goff JP. VCNA‐FAP, July 

2000, 16(2), p331.  PTH=parathyroid hormone, CT=calcitonin, +/‐ indicate influence and magnitude

*PTH causes bone resorption, renal and salivary P excretion but what stimulates PTH release? So how does milk fever affect phosphorus?

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By reviewing and comparing the flow charts above you can recognize how hypophosphatemia frequently occurs in conjunction with hypocalcema. Other problems associated with hypophosphatemia are Rickets/osteomalacia, Chronic hypophosphatemia, acute hypophosphatemia and postparturient hemoglobinuria. Consider the factors altering phosphorus homeostasis to be similar to that of calcium, in addition to a stronger emphasis placed on dietary availability.

Diagnosis:Signalment, History and Clinical Signs, with accompanied low serum phosphorus concentrations Conditions associated with low Phosphorus: Rickets/Osteomalacia: Rickets is a disease of the young where the growth plates fail to mineralize as well as the osteoid matrices of the bone. Osteomalacia is the term used in adults due to the lack of growth plates. Either condition can result from a lack of dietary phosphorus or low plasma calcium (dietary deficiency or vit D deficiency), or combination. The condition arises mainly due to an abnormal ratio of calcium:phosphorus in the body necessary for mineralization. Growth defects and rubbery bones are seen in young animals and pathologic fractures seen in adults. Young animals show depressed growth rates, possibly narrow chests with palpable hard swellings at the costal-chondral junctions of the ribs. Chronic hypophosphatemia: Dietary deficiency of P leading to chronic unthrifty “poor doers”. With vague clinical signs generally affecting the herd, analyze the diet since serum P will likely be normal or low normal. Dietary requirements should contain at least 0.35% P. Acute hypophosphatemia: Consider as a differential diagnosis in “downer” beef cattle in late gestation or at calving, or in “downer” dairy cattle non-responsive to calcium therapy or with normal calcium levels. Plasma P will show a precipitous decline as it increasingly becomes incorporated in fetal skeletal development (cows with twins will more likely show clinical signs). However marginal animals may show clinical signs when lactational demands stress the P levels. Disease is also complicated by low Calcium, magnesium and glucose. Hypocalcemia (PTH release) itself may lead to further loss of serum P in urinary and salivary secretions. If a total body deficit of P is not present, treatment with IV calcium will result in a decrease in PTH secretion and thus loss through saliva and urine. Clinical presentation is similar to pregnancy toxemia seen in small ruminants. Treatment of total body deficits of P, however, requires replacing needed P, which may not be in a readily available formulation of most common combination fluids (see below for treatment recommendations for replacing P). Postparturient Hemoglobinuria: Anemia and hemoglobinuria may develop as a result of intravascular hemolysis from increased RBC fragmentation. It is most frequently seen in cows within the first 6

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weeks after calving and they are frequently (not always) hypophosphatemic. It is likely due to a combination of dietary and metabolic factors since not all hypophosphatemic cows in other stages of lactation with similar deficiencies develop hemoglobinuria. The “theory” is that the deficiency of P to power ATP regulated sodium pumps in RBCs leads to expansion and bursting of the cells as they pass through capillary beds. But why only at this stage of lactation? Why are ketosis cows at greater risk? Don’t know, but questions you should ask yourself and maybe someday you can tell me.

Clinical Pathology: Normal serum Phosphorus is 5 to 9 mg/dl. -Chronic hypophosphatemia cases (mainly failure to thrive) will usually have a serum phosphorus somewhere between 2 to 4 mg/dl. - Acute hypophosphatemia cases (downer cows) should have a serum phosphorus less than 1mg/dl to be considered down as a result of suppressed phosphorus levels.

Treatment: NEED Phosphate ****Main point I want you to recognize is that many commercially prepared solutions contain hypophosphite as the source of phosphorus for replacement therapy. This is because hypophosphate solutions will precipitate with calcium in solution. The problem is that hypophosphite is NOT biologically active and is thus ineffective in phosphorus replacement. So you need to replace phosphorus with a phosphate solution (just don’t mix it with calcium to give IV). Fortunately this has been recognized and plenty of oral products (gel tubes) supply phosphorus in the form of phosphate. Read the label. -IV Phosphate. 30gm of monosodium phosphate or 90gm of disodium phosphate dissolved in 300 to 500 ml of distilled water respectively. The effect of IV phosphorus replacement is only short lived (a few hours). -Oral Phosphorus replacement provides a longer and more sustainable source for treatment. 500gm of monosodium phosphate dissolved in 3 to 4 gallons of warm water is effective and will provide a sustained source of P for 12 hours. An oral source should be administered after IV. Suitable oral P will increase plasma levels within 1 hour if rumen motility/function is not severely impaired.

Prevention: Know risks: Mature late season pasture is usually low in P. Cows with other metabolic diseases. Late gestation beef cows on mature pasture. Diet: Needs to provide sufficient P. Grains and mineral supplements are excellent sources of P.

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Magnesium (“Grass Staggers/Grass Tetany”) Magnesium is another essential mineral where dietary and metabolic derangements lead to common clinical syndromes in cattle. Magnesium plays huge roles in enzymatic activity (ie ATPases, kinases, etc), protein synthesis, membrane channel regulation, and modulates neuromuscular synaptic transmission. So, like the other metabolic diseases we have discussed thus far, errors in homeostasis can obviously lead to devastating clinical disease. However, one big difference to note with magnesium, is that it is NOT regulated under specific hormonal control, unlike calcium for example.

There are large body stores of magnesium (mainly bone), however the extracellular magnesium pool is dependent upon daily GI absorption. The amount of magnesium absorbed from the GI tract must meet that which is lost each day via endogenous losses (ie milk, urine, GI) see figure 3. What is absorbed daily will exceed the relatively constant extracellular pool by greater than 5X to compensate for daily losses or the animal becomes at risk for deficiency. Endogenous losses into the GI tract and milk continue independent of Extracellular fluid concentration, even when low (no direct hormonal mechanism to regulate bone redistribution or excretion). The kidneys can rapidly adjust the amount of magnesium being excreted to rid the body of surplus, but not fully compensate for deficiency.

 

Figure 3. Simplified schematic drawing to demonstrate that inflow must at least meet outflow, with excess being 

excreted by urine.  A constant turnover exists between bone/tissue and ECF but is not up or down regulated in 

times of need.    Chart adapted from: Martens H, Schweigel M. VCNA‐FAP, Jul 2000, 16(2), p340. 

*Magnesium homeostasis is dependent upon daily GI absorption from the diet. Where is Mg primarily absorbed in the adult? Calf? What may alter absorption of dietary magnesium?(Hint: other dietary imbalances) What other risk factor(s) may lead to hypomagnesemia?

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Magnesium absorption: If there is a daily need for magnesium and it must be absorbed from the GI tract where does this occur? In the mature ruminant, Mg is absorbed almost exclusively through the rumen (a little by the omasum) epithelium by trans- and paracellular pathways. Calves absorb Mg through the small and large intestine until the rumen develops. Though adult cattle maintain the ability to absorb magnesium through the intestine, this compensation does not occur if hypomagnesemia develops. Rectal infusions of magnesium formulations will increase serum magnesium concentrations and has been recommended as a method of treatment. Mg absorption is driven to some extent by a small chemical gradient (paracellular) and mostly by a large electrical potential difference (transcellular). These two mechanisms work well when rumen Mg concentrations are low. Absorption independent of a potential difference (ie co-transport with anions) is likely working when rumen Mg concentrations are higher. A combination of absorptive pathways are necessary, due to constantly fluctuating rumen magnesium concentrations and a need for constant inflow of Mg to the extracellular pool. Here are the points of all this technical jibber jabber. 1. Magnesium is absorbed in the rumen and the animal needs a constant daily supply, therefore needs an adequate dietary level of magnesium. Low magnesium intake (such as that seen in early spring grasses) puts animal at risk for hypomagnesemia. Feed restriction and overexertion may result in hypomagnesemia referred to as “transport tetany”. 2. Changing the electrochemical rumen environment will prevent absorption of the needed magnesium even if dietary intake is adequate (or even in excess in some cases). What changes the electrochemical gradient? Answer… other ions, the big ones I want you to know are potassium excess (in the rumen) and sodium deficiency (systemic hyponatremia). Systemic hyponatremia (as one might see occur in cattle grazing early spring grasses) has a two pronged attack on magnesium absorption. Not only is there little sodium available for an important Na/Mg++ exchange needed to absorb Mg++ into circulation but also hyponatremia leads to aldosterone release. Aldosterone causes reduced Na secretion and an increase in potassium secretion by the salivary glands. Consequently the animal will be swallowing a higher concentration of potassium, thus increasing the rumen potassium concentration. High rumen potassium concentrations results in decreased magnesium absorption by changing the electrical potential difference conducive to efficient magnesium absorption. So fresh spring grasses are both low in sodium and high in potassium. Can you now rationalize some risk factors that will lead to the syndrome of “grass tetany”?

Another recognized risk factor for hypomagnesemia is nitrogen (ie high crude protein), which is also a component of lush spring grasses, but also exacerbated with artificial N fertilizer commonly applied to pastures. The mechanism for increased rumen NH4 (result of increased protein intake), is not completely understood, but sudden

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increases in dietary protein/N will depress serum Mg. This can be reproduced in cattle coming off of winter feed and promptly put onto lush spring forage. The rumen will adapt adequately if protein intake is gradually increased. So thus far, in order to assure adequate magnesium concentrations are achieved, we need to have adequate dietary magnesium intake, a balanced sodium and potassium intake, and adapt to consumption of increased dietary proteins. In addition, energy feeding in the form or fermentable carbohydrates (ie grain) will lower rumen pH and promote rumen papillae development, both of which enhance magnesium absorption.

Diagnosis: History, Signalment, Clinical Signs, Response to Therapy History/Signalment: Most commonly seen in lactating beef cattle grazing lush spring grasses (Grass tetany). Can be seen in cattle that have been transported distances with feed restriction (transport tetany). May be seen in late gestation cows receiving inadequate energy intake such as in late winter (winter tetany). Hypomagnesemia may be seen in cattle (often yearlings) grazing early growth wheat pasture or other early growth cereal pastures (wheat pasture tetany). May be seen in calves (>2months) fed only milk or replacers after rumen development (milk tetany). Dairy cattle may develop hypomagnesemia when dietary magnesium is either deficient, fed in a poorly bioavailable form, or provided diets altering absorptive mechanisms as discussed above. Clinical Signs: Generally progressive dependent upon the degree of magnesium suppression and if the animals are also experiencing concurrent hypocalcemia (common). Smoldering herd problems (beef and dairy) resulting in poor milk production, nervous/agitated cows, poor milk fat, etc., may indicate hypomagnesemia. When you see clinical cases, it is due to neuromuscular dysfunction. Moderate to severe hypomagnesemia is manifested early as twitching of the face/shoulders/flanks and irritability progressing to a spastic/stiff gait, polyuria, and manic bellowing and finally titanic spasms, staggering, falling and convulsions. They may be profusely salivating and clamping their jaws. Elevated TPR is noted due to the extreme muscular exertion. Waxing and waning of clinical signs may be observed until death if not treated. Clinical Pathology: You may consider measuring magnesium concentrations in some situations, particularly chronic herd problems and during post-mortem exams. It is really difficult and not very useful to try to measure serum/plasma magnesium in clinical cases, which may actually be normal due to muscle activity and damage. Plasma or serum concentrations between about 1.2 to 1.8 mg/dl indicate inadequate magnesium absorption and may support herd problems. Cattle with magnesium levels below 1

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mg/dl are at risk for tetany. CSF and vitreous humor concentrations and are reliable indicators of magnesium status for 12 hours and 24-48 hours post-mortem respectively. Treatment: USE EXTREME CAUTION when approaching/handling these cattle as they can often be quite aggressive. If these cattle appear comatose when you approach, they may be in between cycles of clinical signs, “resting for the next run” so to speak. They are often hyper-excitable to noise as well. Be quiet, calm, and efficient and plan your exit strategy before you start. -Intravenous Magnesium Solutions: (only chance for Tetanic/convulsing/down cows). Magnesium hypophosphite, Magnesium borogluconate, Magnesium chloride, or Magnesium gluconate. Administer solutions containing Magnesium as well as Calcium. These cattle are almost always hypocalcemic as well, and the added calcium during treatment helps prevent cardiac arrest. DO NOT sedate before treatment which may cause death from hypotension. 500ml of a commercially prepared combination solution is sufficient for adult cattle. Don’t administer the solution too fast. Leave the cow alone after treatment and, IF she is going to recover, expect response to therapy in ~30min to 1hr. -Subcutaneous Magnesium Sulfate: For preventing relapses as well as mild cases of hypomagnesemia. Give 100-200ml SQ, with no more than 50ml per site. -Enemas: Preventing relapses and possibly cases where accessing a vein for IV treatment is not possible. 60gm of Magnesium chloride or Magnesium sulfate dissolved in a minimum of 200ml of H2O. Need to administer it as proximal to the rectum as possible (ie. descending colon). May cause some mucosal irritation and sloughing. Will elevate plasma magnesium within 15 minutes. -Oral Magnesium Salts: Only give when animal is stable enough to maintain esophageal reflexes especially if a liquid solution is to be mixed up in a drench. Oral Gel tubes are available for cattle. Oral salts provides a more prolonged method of maintaining magnesium concentrations to prevent relapses. In addition, adding calcium carbonate, dicalcium phosphate, and sodium chloride will provide additional calcium (usually hypocalcemic), bioavailable phosphorus (frequently hypophosphatemic), and enhance magnesium absorption(NaCl). The best oral form (most available) of magnesium is Magnesium sulfate. Whatever oral solution you give should provide at least 50grams of Magnesium. Read the label, 100g of magnesium oxide for example, only provides 50 g of magnesium.

Prevention: Needs to be discussed soon after the first clinical case is diagnosed. We need to figure out how to get an additional 15 to 30 grams of magnesium per day into the cows. Doesn’t seem like a big deal, but free choice magnesium salts are not palatable. Drenching each cow every day is not practical as might be the additional cost of grain to

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mix and feed. High magnesium mineral blocks and supplements are available, but the cattle still have to eat them. Recommendations:

1. Feed mature grass or legume hay. Improves dry matter intake thus improving magnesium intake. Hay generally higher in magnesium (also lower in potassium) than early spring grass, but the cattle will generally prefer the grass. Therefore, may require confinement feeding. May even consider top dressing or mixing with the hay 60g mg oxide/molasses/cow.

2. Spraying pasture with magnesium oxide. 3. Add 10lb mg sulfate (Epsom salts) to 500 gal water trough. Just make sure

they are willing to drinking the water mixture if no other water source is available and/or not from the stream/pond next to it.

4. Magnesium supplement licks and blocks are great if the cattle have learned to use them, preferably before the problems are occurring.

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Energy (Negative Energy Balance) ”Ketosis” Ketosis is a clinical sign as well as a disease associated with negative energy balance (NEB) and mobilization of fat for energy. The formation of ketone bodies, (acetoacetate, acetone, and β-hydroxybutyrate) for energy, defines ketosis. NEB is extremely common in recently postpartum dairy cows due to extreme energy demands for lactation. Ketosis occasionally occurs prepartum in beef cows resembling pregnancy toxemia in small ruminants, and is associated with NEB due to poor quality feed and decreased feed intake prior to calving. An important point to make is that in dairy cows, lactation peaks at about one month whereas maximal feed intake does not peak until about 2 months post freshening. It’s not uncommon for dairy cows to lose 200 to 300 lbs within the first couple months of lactation. Pathophysiology: -Carbohydrates, Protein, Fat area derived from the diet and constitute body fuel sources for energy. Non-esterfied fatty acids (NEFAs) and Ketone bodies are derived from metabolized body fat as extra fuel sources when needed. Positive Energy Balance (PEB): Carbohydrates and nutrients from dietary intake can meet energy demands. Negative Energy Balance (NEB): Carbohydrates cannot be stored in sufficient amounts to meet energy demands and therefore must either be synthesized from body protein or fat must be used as an alternative energy source. The latter is favored in order to protect from depletion of body protein, primarily skeletal muscle. Carbohydrates cannot be synthesized from fat. Using fat as an alternative energy source, conserves body protein and carbohydrate which is needed to meet lactational demands. Conservation of carbohydrate is required to allocate its use for milk production since the mammary gland requires carbohydrate for the production of lactose. Gluconeogenesis meets milk production carbohydrate demands using propionic acid as the precursor. Also, glucose is utilized in muscle, nervous tissue, the fetus, as well as in lipolysis and lipogenesis (glycerol). Rumen fermentation greatly decreases the amount of carbohydrate absorbed from the GI tract (resulting in a net loss of carbohydrate) and propionic acid is the only fatty acid able to support gluconeogenesis. Remember the other two volatile fatty acids produced during rumen fermentation are acetic and butyric acids, but they cannot be used in gluconeogenesis. Skeletal muscle adapts to using fat derived energy sources (NEFAs and Ketones) to conserve carbohydrates as well as protein. So, with gluconeogenesis being limited and primarily supporting lactation demands, the ruminant must utilize other sources for energy and conserve body protein during NEB.

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I. Adaptation to NEB (What should happen) NEFAs

A. Recycling of Fatty Acids and Adipocytes Mobilization of fat stores, results in the release of NEFAs to be utilized as energy in

body tissues, except for mammary gland or the fetus, as these sites are dependent on glucose and amino acids. See figure 4, recycling of fatty acids within the adipocytes. The rate of fat turnover within the adipocytes regulates the rate of NEFA release into the blood. Low blood glucose results in more NEFAs entering the blood. Why? Since less glucose is available for glycerol synthesis (necessary for lipogenesis within the adipocytes), the result is more lipolysis and less lipogenesis.

B. The Liver in NEFA metabolism: Ketones are produced in the rumen epithelium, mammary gland, kidney cortex and

the liver, however the liver is the primary organ involved in ketogenesis. The liver removes a large amount of NEFAs from circulation and either oxidizes them to ketone bodies or re-esterifies them into triglycerides. What NEFAs the liver does not remove are utilized by muscle for energy. The glucose availability is an important determinant in which pathway NEFAs take within the liver. During times of high glucose availability (ie adequate dietary carbohydrate) and high NEFA concentrations (ex obese cows), triglycerides formation is favored and may possibly result in fatty liver. Whereas, when glucose concentrations are low and NEFA concentration is high, oxidation to ketones is favored. Ketones are utilized as an alternate energy source.

Figure 4:  NEFA metabolism and adipose cycling.  Compiled from Herdt, VCNA‐FAP 16(2) 2000, p217. 

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C. The endocrine system: The endocrine system is essential for regulation, not alteration of the metabolic

adaptation to NEB. Insulin, Glucagon, epinephrine, norepinephrine, and growth hormone are the hormonal mediators in the regulation of the metabolic process in adaptation to NEB.

1. Insulin (glucoregulatory as well as liporegulatory) - NEFAs and Ketones stimulate insulin release, which results in more

lipogenesis and inhibits lipolysis. The result is declining blood NEFAs and ketones which decreases insulin release. (negative feedback)

- Concentration influenced by glucose and propionic acid (glucose precursor)

- Blood concentrations fall in NEB

2. Glucagon (counter-regulates insulin) - Stimulates gluconeogenesis in the liver - May stimulate lipolysis in some species, but verdict still out on ruminants?

3. Catecholamines (*Lipolysis)

- Sympathetic nerve endings in adipose tissue, causes an increase in circulating NEFAs

4. Growth hormone

- Decreases lipogenesis (increases blood NEFAs), and is stimulated by hypoglycemia.

II. Failure of Adaptation to NEB (ie development of Ketosis and Fatty Liver)

Distinct types of ketosis occur. Different ways of classifying the types of ketosis are described. It’s important to recognize these classifications because when we talk about treatment, not all cases respond to a dose of sugar solution. You will have to be able to rationalize why in practice in order to explain to your client why an individual may not be responding and what the next step should be. I use a combination of A and B below as far as describing Ketosis and rationalizing treatment or treatment failure. Letter C below is for your information only as it is still more speculative than accepted, but who knows what the future holds? Primary vs. Secondary

a. Primary (ex., inadequate diet, overwhelming adaptive mechanisms) i. Alimentary- dietary origin (ex. Too much protein, too little carbs) or

some other imbalance

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ii. Hepatic- liver unable to cope with fatty acids or provide adequate gluconeogenesis. May indicate fatty liver.

b. Secondary (some other condition decreases feed intake) i. Examples; Displaced abomasum, mastitis, metritis, lameness, etc.

B. Periparturient vs Peak lactation

a. Periparturient- fatty liver development prior to calving from NEFA esterfication, decreasing gluconeogenesis, and shift in the liver to ketone production.

b. Peak lactation- insufficient gluconeogenic substrate to support milk production demands

C. Type I vs. Type II : This classification method is derived from the similarities that

ketosis shares with type I (insulin-dependent) and type II (insulin-resistant) diabetes mellitus. There is hesitation by many to accept this method, as rarely are cows hyperglycemic and hyperinsulinemic (type II) when diagnosed with ketosis. However evidence shows that these events may occur prior to clinical disease.

a. Type I Ketosis: Glucose demand outweighs the liver’s gluconeogenesis capacity. Resembles type I Diabetes mellitus in ketone production and insulin status.

i. High blood ketones without fatty liver ii. Maximal gluconeogenesis stimulation but not enough substrate iii. Blood glucose and insulin are low. iv. NEFAs being primarily used for ketogenesis, little esterfication v. Occurs at time of peak lactation

b. Type II Ketosis: High blood NEFAs without adequate gluconeogenesis or ketogenesis.

i. High blood ketones with fatty liver development ii. Gluconeogenesis and ketogenesis are not maximally stimulated iii. Fewer NEFAs being oxidized to ketones, more being esterified to

triglycerides and accumulating in liver. iv. Occurs shortly after parturition, before peak-lactation v. Less responsive to treatment (refractory) vi. Similar to type II diabetes mellitus, with hyperglycemia,

hyperinsulinemia, and insulin resistance.

D. Nervous Ketosis: A fourth classification of ketosis you may encounter is “nervous ketosis”. However this is less a classification but more appropriately a description of clinical signs associated with CNS stimulation associated with

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circulating ketones and hypoglycemia. This form is manifested as excitement, hyperesthesia, hypermetria, ataxia, deprave chewing and licking.

Diagnosis: History, Signalment, Clinical Signs, and detectable urine/milk ketones

I. Signalment and History Fat cows are more likely to develop Periparturient or Primary ketosis, whereas

thin cows are those most often affected with peak-lactation types of ketosis. Conditions predisposing cows to secondary ketosis can occur in both thin and obese cattle with obese cattle possibly being more dramatically affected or developing fatty liver. Changes in weather, ration composition, and managerial changes may indicate the likelihood and severity of ketosis. A marked decrease in milk production or failure to produce adequate quantities of milk post calving, are often revealed in the history.

II. Clinical Signs General depression and varying levels of feed intake and mild dehydration may

be all that is noted on general physical exam. A distinct ketone breath odor can be detected by some individuals, but not all of us can smell ketones. If nervous ketosis is encountered, clinical signs will be as previously described. If ketosis is subclinical, decreased feed intake (particularly concentrates), dry feces, decreased milk production, and increased incidence of disease may be observed on an individual or herd basis.

As ketones can suppress immunity, examination for metritis, mastitis, pneumonia, etc should be performed. (A complete exam should be performed anyway). Interrelationships between ketosis and association with development of abomasal displacements, metritis, mastitis and overall white blood cell function have been debated as to cause and/or effect.

III. Diagnostics Hyperketonemia, ketonuria, ketolactia, hypoglycemia, and elevated blood NEFAs are indicative of ketosis. A. Semi quantitative testing. The most common methods for testing animals for the presence of ketones are

the semiquantitative dipsticks and powders. These tests give an estimate of the severity of ketosis (clinical cases) based on the intensity of the color change on the dipstick or of the powder used. These tests can either be used to test milk or urine. Testing the urine is more sensitive than milk in detecting ketones. False positives can arise when testing urine in that urine ketones are about 4X higher than blood concentrations and some urine metabolites may react with the test. Testing the urine only measures acetoacetate. Milk tests have the ability of being more specific but less sensitive. Milk tests may be a nitroprusside test which detects acetoacetate, or another

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milk test (Ketolac®) tests for β-hydroxybutyrate. Colostrum may decrease the sensitivity of the milk tests further.

B. Quantitative testing. Used for detecting subclinical ketosis primarily. “Smoldering herd problems” may

stimulate quantitative subclinical ketosis evaluation. Measuring serum β-hydroxybutyrate is preferred as it is stable in tissues and blood samples, whereas acetoacetate readily breaks down. In order for quantitative tests to be of use, consistent thresholds have to be available to interpret test results. There is a lot of variation in what constitutes a threshold limit for detecting subclinical and clinical ketosis, and also variation in cows that show clinical signs at different levels. Serum β-hydroxybutyrate concentrations greater than 1000µmol/L (10.4mg/dl) to 1400µmol/L (15mg/dl) indicate subclinical ketosis. Concentrations of 2000µmol/L (21mg/dl) to 2600µmol/L (27mg/dl) are consistent with clinical ketosis. When measuring β-hydroxybutyrate it is important to note that whole blood and serum produce the above results, whereas measuring plasma will result in lower values. Also RBC lysis in a serum sample will elevate results.

C. Serum Biochemical Abnormalities. Interpreting serum chemistry results can be misleading in determining severity of

hepatic lipidosis and ketosis. Biochemical evidence of liver disease is inconsistent in determining the intensity of treatment required to treat the animal. A combination of hypoglycemia, decreased total CO2, and elevated AST is the most helpful in determining severe lipidosis in cattle. Elevated SDH and bilirubin are poor indicators of severity of disease.

Treatment: Goal: Decrease ketogenesis and reestablish glucose homeostasis.

1. Intravenous bolus of 50% dextrose. Most common initial attempt. a. How much???? Treatment bottles come in 500ml containers and

historically it was recommended to give the full bottle IV. That method is no longer recommended. The renal threshold for glucose in cattle is about 100mg/dl, and giving a rapid IV bolus at that volume exceeds the threshold resulting in the majority of the glucose lost in the urine and actually some diuresis. The result may be to worsen the problem. Therefore boluses should be restricted to ½ (~250ml) of a bottle and repeat in about 6 hours.

b. More is NOT better with bolus treatment. c. Relapse is common.

2. Continuous IV Glucose infusion a. Administer a 2.5 to 5% dextrose solution as a CRI for at least 24 hours.

We are not worried about fluid volume in these cases, but supplying a

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basal source of dextrose over an extended period to allow the body to equilibrate the metabolic problem. Sometimes it requires 2 to 3 days of treatment. Stop when cow is eating well and ketones are decreasing.

3. Glucocorticoids a. Contrary to popular belief that exogenous steroids work by primarily

stimulating gluconeogenesis, this is not the primary mechanism of action. The main benefit is slowing milk production and affecting glucose distribution and kinetics

b. Dose: 10mg to 20mg Dexamethazone (450 to 500kg cow) 4. Insulin and Glucocorticoid combination

a. 100 to 300 IU of long acting insulin. Max 2 doses, 48 hours apart. b. Use in combination with dextrose therapy (preferably CRI) and

glucocorticoids to prevent hypoglycemia. 5. Oral Glucose Precursors

a. Propylene Glycol (~10oz) once or twice daily b. Will interfere (kill off) rumen microbes with chronic or excessive use c. Toxic levels can result with excessive dosing

Prevention: Key: Prevent obesity, maximize feed and energy intake in early lactation, and provide adequate glucose precursors. 1. Feed intake

a. Constant Feed Availability b. Decrease feed bunk competition

2. Rations a. Well balanced nonstructural carbohydrate rich rations to promote

proprionate formation and uptake b. High moisture silages promote fermentation to butyric acid which is

unpalatable and easily converted to β-HB and absorbed c. Balanced ration to prevent carbohydrate overload leading to acidosis. d. Dry cows should be fed to maintain weight. e. Transition rations- increase dry matter intake last 2-3 weeks of dry period

to prepare rumen for adaptation to fresh cow ration 3. Decrease Stress

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Potassium. All I want to emphasize about Potassium in this block of lecture is a recognized syndrome of severe hypokalemia that we occasionally encounter in adult dairy cattle, resulting in severe muscle weakness and inability to rise. You will certainly deal with the more common occurrence of hypokalemia when talking about acidosis and diarrhea in calves (Dr. Jones in neonatology), as well as a secondary “gee whiz” associated with various illnesses. But this less common syndrome needs to be discussed if only for recognition and another differential for refractory cases of milk fever, magnesium, phosphorus, ketosis etc. Hypokalemia Syndrome in Dairy Cattle. Characteristics:

-Holsteins are most commonly represented (rarely other breeds), heifers up to aged cows. -Almost always within the first 45 days of lactation (a few outliers) - Chronic ketosis, mastitis commonly in history. Being repeatedly treated for ketosis (bolus treatments) results in duresis and potassium loss. Chronic mastitis may result in prolonged anorexia. -hepatic lipidosis often found in severe cases at necropsy. -History of receiving multiple (3-5) doses of isoflupredone acetate (Predef®). In one study it was in the history of 10/15 cases of hypokalemia syndrome. This is/was a commonly used steroid for “empirically” treating a multitude of ailments, or conditions (one being udder edema). Almost all cases of this condition where isoflupredone acetate was used had a history of the drug being used in a non-label compliant way. Too many doses, multiple intramammary infusions, IV, etc. Isoflupredone acetate has a much stronger mineralocorticoid effect with enhanced urinary and GI loss. To date, it may increase the risk of disease significantly, but is not required to cause disease. -multiple doses of dexamethazone in previous history is not uncommon. (interestingly has little to no mineralocorticoid effect) -Case mortality rate is about 60% in intensively treated cases. -Serum potassium levels in clinical cows are <2.1mg/dl (mEq/L). -The serum potassium represents an extreme total body deficit. *Consider this a potential problem in cows that have been chronically treated for ketosis, had prolonged anorexia, received multiple doses of steroids and are in the first couple of months of lactation.* Treatment: Both IV and Oral required. Monitor Mg and P during treatment. Treat until she gets up. -Isotonic IV KCl. Do not exceed rat of 0.5mEq/kg/hr -Oral KCl. Don’t exceed 0.5lb orally bid, but get as close as you can. Excessive hyperosmotic KCl will induce diarrhea as well as reduce magnesium absorption.